Agricultural compositions and use



United States Patent 2,988,478 AGRICULTURAL COMPOSITIONS AND USE Philip N. Gordon, Old Lyme, Conn., assignor to Chas. Pfizer & (30., Inc., New York, N.Y., a corporation of Delaware No Drawing. Filed Dec. 22, 1958, Ser. No. 781,897 5 Claims. (Cl. 167-33) This application is concerned with new and useful anti-pathogenic compositions containing certain long chain alkyla-mino or alkenylamine derivatives of five, six, seven and eight membered ring compounds containing two nitrogen atoms in the ring. It is concerned also with the use of these valuable compounds in the treatment of various pathogens.

It has now been discovered that certain 2-a1kyl and 2 alkenylaminoimidazoles, imidazolines, pyrimidines, 1,4,5,6 tetrahydropyrimidines, 4,5,6,7-tetrahydro-1,3-diazepines and 1,3-diazacyclooctenes-2, various substituted derivatives of these, as explained more fully hereinafter, quaternary alkyl ammonium derivatives of these, as well as their acid addition salts are useful anti-pathogenic agents for the control of various pathogens including animal pathogens and those which infect human hosts, but particularly useful in the control of phytopathogenic agents which attack plants.

The free bases which, together with the corresponding acid addition salts and quaternary alkyl ammonium salts constitute the active agents in the useful compositions of the invention are represented by the formula t wherein R is selected from the group consisting of alkyl and alkenyl groups containing from one to eighteen carbon atoms; n is an integer from two to five; R is selected from the group consisting of hydrogen, alkyl and alkenyl containing from one to six carbon atoms, the total number of carbon atoms in said R and R being from six to twenty-four. Also included in the purview of the invention are compositions containing =further compounds of the class defined above wherein n is two or three and adjacent carbon atoms in the heterocyclic ring form a conjugated system. In a quaternary compound of this invention an alkyl group contains from one to four carbon atoms.

The specific acid addition salt which is used in pre paring the compositions of this invention will depend upon the particular application of the composition. Thus an acid addition salt which is acceptable in agricultural practice may be too toxic for other uses and one which may have solubility characteristics especially suitable for preparing liquid compositions may not be the most desirable for solid compositions.

Compounds useful for the preparation of compositions of this invention include Alkylaminoimidazolines Alkenylaminoimidazolines Alkylaminoimidazoles Alkenylaminoimidazoles Alkylaminopyrimidines Alkenylaminopyrimidines Alkylaminol ,4,5 ,G-tetrahydropyrimidines Alkenylamino-1,4,5,6-tetrahydropyrimidines Alkylamino-4,5,6,7-tetrahydro-1,3-diazepines A1kenylamino-4,5,6,7tetrahydrp-1,3-diazepines Alkylamino-l ,3-diazacyclooctenes-2 Alkenylamino-1,3-diazacyclooctenes-2 Certain derivatives of these compounds are also useful 2,988,478 Patented June 13, 1961 anti-pathogenic agents. For example, the acid addition salts and quaternary alkyl ammonium salts wherein the alkyl group contains from one to four carbon atoms may be successfully employed in the treatment of various pathogenic conditions. Compounds of this invention can be prepared as N-alkyl substituted derivatives which can also be converted to acid addition or quaternary salts. These too are useful in the preparation of anti-pathogenic compositions.

It is an essential feature of this invention that the total number of carbon atoms in alkyl and alkenyl groups attached to an exocyclic nitrogen atom excluding the alkyl group of a quaternary salt, be at least six. Thus, if there is no heterocyclic N-alkyl or alkenyl substituent, the alkyl or alkenyl group attached to an exocyclic nitrogen atom will contain at least six carbon atoms. On the other hand, if there is a heterocyclic N-alkyl or alkenyl group, the total number of carbon atoms in this group and the exocyclic N-alkyl or alkenyl group should equal at least seven. In any case, the total number of carbon atoms in these alkyl or alkenyl groups will not exceed twenty-four carbon atoms.

The compounds which are used in this invention are readily prepared. One method of preparation involves simply heating an alkyl or alkenylamine with an acid addition salt, usually although not necessarily the hydriodide, of a 2-alkylmercapto substituted imidazole, imidazoline, pyrimidine, tetrahydropyrimidine, tetrahydrodiazepine or 1,3-diazacyclooctene-2. For the preparation of the simpler compounds, that is, those in which the only substituted nitrogen atom is an exocyclic nitrogen atom, the selected mercapto compound will be a methylmercapto compound. Compounds of this nature in which the heterocyclic ring contains five or six carbon atoms are well known. Those in which the ring contains seven or eight carbon atoms are prepared by the same method used to prepare the tetrahydropyrimidine, that is, by reaction between carbon disulfide and a diaminoalkane, for example, 1,4-diaminobutane or 1,5-diaminopentane. By selecting an N-alkyl or alkenyl diaminoalkane the resulting Z-methylmercapto compound will carry an alkyl or alkenyl substituted heterocyclic nitrogen atom, for example, Z-methylmercapto-N-(Elhexenyl)-1,4,5,G-tetrahydropyrimidine. This compound and similar compounds can be reacted with an amine to prepare the compounds useful for this invention. These reactions are all well known to those skilled in the art.

Obviously by proper selection of the diamino compound it is possible to prepare substituted heterocyclic compounds including, amongst others, alkyl substituents having up to four carbon atoms, cyano groups, halogen atoms or hydroxyl groups. Similarly substituted imidazoles and pyrimidines can be prepared by known reactions. In fact, the alkyl or alkenylamine used to prepare the final compounds of this invention may itself be substituted provided only that the substituent does not interfere with the course of the reaction. Thus, if the amine chosen is unsymmetrically substituted with another amine group, it is obvious that more than one compound can result. On the other hand, amino, ether or ester groups will not interfere with the reaction. Although these substituted compounds appear to have comparable activity, they are not generally preferred for the preparation of the valuable compositions of the invention because in many instances they are somewhat more difiicult to synthesize and are more costly.

It is obvious that the Z-methylmercapto heterocyclic compounds are not the only compounds which can be used to prepare the valuable agents of this invention. In fact, theoretically any 2-alkylmercapto compound can be used, even one containing as many as six carbon atoms. However, the 2-methyl compound is generally preferred because it is less expensive to prepare. Further if the Z-methyl compound is used the by-product methyl mercaptan is volatile and easy to remove from the reaction mixture.

In carrying out the reaction, the compounds are mixed together and heated at from about 80 C. to about 120 C. for a period of from about four to about twentyfour hours. It is not necessary to use an excess of either reactant, in fact, it is preferred not to do so since removal of unreacted starting material may complicate the purification procedure. However, small molar excesses, say up to of either reagent can be tolerated and may even be desirable if the reagent not used in excess is particularly expensive. At the end of the reaction period, the reaction mixture is cooled and the desired product usually crystallizes from the melt. Crystallization may be aided by trituration with ice cold ether. The reaction product is usually quite hygroscopic and picks up moisture readily. For this reason it may be difiicult to induce crystallization or, in fact, to maintain the crystals once they have formed. However, the valuable properties of these compounds are not impaired by the presence of moisture or by their physical state.

Although the reactions described above can be employed for the preparation of the aromatic compounds of this invention, namely the imidazoles and pyrimidines, it is preferred to prepare these compounds by treatment of a Z-aminoimidazole or 2-aminopyrimidine with an alkyl or alkenyl halide. This reaction is conveniently carried out by taking up the Z-arnine compound in a lower aliphatic oxygenated solvent containing up to five carbon atoms such as acetone, methanol or ethanol and adding at least an equivalent of the selected alkyl or alkenyl halide, preferably as the bromide or iodide. The reaction mixture is allowed to stand at about C. to about C. for from about eight to about seventy-two hours. At the end of the reaction period, the product is isolated by evaporating the solvent in vacuo. It is best that no heat be employed in carrying out the reaction since increased temperatures may lead to undesirable side reactions, especially rearrangements.

The free bases of this invention are readily prepared from the acid addition salts synthesized as described above. One especially useful process is to dissolve the acid addition salt in water and to make the resulting solution basic with an alkaline reagent, for example, 5-l0% aqueous sodium hydroxide, carbonate or bicarbonate. The nitrogen-containing free base is recovered by extracting the solution with a suitable solvent. Useful extraction solvents include hydrocarbon and halogenated hydrocarbon solvents containing up to six carbon atoms and ethers containing up to eight carbon atoms. Diethyl ether, di-n-butyl ether benzene, chloroform and ethylene dichloride may be mentioned by way of example of the extraction solvents which can be used.

Other acid addition salts are prepared by methods well known in the art. The hydrochloride, for example, can be prepared by dissolving the free base in ether and adding anhydrous hydrogen chloride. For certain applications it may be desirable to utilize acid addition salts other than halogen acid addition salts. For example, it may be desirable to prepare sulfate, nitrate, phosphate, citrate, gluconate or tartrate acid addition salts. These may be prepared by procedures well known to those skilled in the art. One method which is highly useful with water soluble acid addition salts comprises contacting the halogen acid addition salt with the acid form of a basic anion resin such as the highly basic compounds provided by the Rohm and Haas Co. under the trade name Amberlite IRA-400. This resin is a polyquaternary ammonium compound which is prepared by chloromethylating a highly cross-linked copolymer of styrene and divinyl benzene followed by treatment of the chlorornethylated material with a tertiary amine such as trimethylamine. To prepare a tartrate, for example, the

resin is first contacted with an aqueous tartaric acid solution and an anion exchange takes place converting the quaternary halide to the tartrate. The tartrate resin is then contacted with a halogen acid addition salt of this invention and a further ion exchange takes place converting any halogen acid addition salt to the tartrate and leaving the halide ion on the resin. The tartrate salt then can be recovered from the eluate by a number of methods as for example, evaporation or solvent precipitation. This same procedure can be used to prepare sulfate, nitrate, phosphate, citrate, acetate and other acid addition salts.

A quaternary alkyl ammonium halide salt of this invention is prepared in the usual manner. A methanol or ethanol solution is prepared containing at least an equivalent and preferably an excess of an alkyl halide containing up to four carbon atoms together with the compound to be quaternized, the latter in the form of a free base. Generally, the desired compound will form by allowing the reactants to stand at about 25 C. for from about one to about twenty hours. Reaction may be hastened by refluxing. Often the quaternary salt will precipitate as it is formed, but since the compound may be somewhat soluble in the reaction solvent it is best to recover the product by removing the solvent in vacuo.

Other quaternary alkyl ammonium salts of this invention can be prepared utilizing the basic anion exchange resin referred to above in connection with the preparation of acid addition salts. Thus for example, a quaternary tartrate can be prepared by passing a quaternary alkyl ammonium chloride over an anion exchange resin of the class described above which has been treated previously with aqueous tartaric acid. A number of valuable quaternary alkyl ammonium salts can be prepared in this manner including the acetate, propionate, valerate, maleate, succinate, gluconate, citrate, itaconate, nitrate, phosphate and sulfate.

As stated above, the compositions of this invention are useful in the control of plant pathogens. They can be utilized in the control of phytopathogenic fungi including Fusaria which cause wilts. They are particularly useful in the control of rusts and mildews caused by obligate parasites.

Wilts are among most difiicult plant diseases to control. Included in the Fusaria caused infections in plants are tomato wilts (F. oxysporum f. lycopersici); cotton wilt (F. oxysporum f. vasinfectum); watermelon wilt (F. oxysporum f. niveum); flax wilt (F. oxysporum f. lini); cabbage yellows (F. oxysporum f. conglutinans); banana wilt (F. oxysporum f. cubense); celery yellows (F. oxysporum f. apii); pea wilt (F. oxysporum f. pisi); pea semi wilt (F. oxysporum f. pisi); muskmelon wilt (F. oxysporum f. melonis); aster wilt (F. oxysproum f. callistephi); broad bean wilt (F. oxysporum f. fabae); and stock wilt (F. oxysporum f. mathioli). In controlling Fusaria caused diseases, the chemical agent of this invention satisfies a long-felt and most important agricultural need. Heretofore in many cases, the only effective control for diseases of this type has been to develop Fusaria-resistant strains of the plants. For example, I. C. Walker in Plant Pathology, McGraw-Hill Book Co., Inc., 1950, states that the only practical means of controlling tomato wilt is by the use 01 resistant varieties of tomatoes. He further states that cabbage yellow is successfully controlled by the use of resistant varieties.

The successful treatment of obligate parasites is an especially insidious problem. Obligate parasites are parasites which will grow only on specific living hosts and will not grow under any other conditions. They are often so specific in their genetic requirements that they will grow only on plants of a particular species. Since they must be on living hosts during their life cycle, it appears that they have lost many of their biosynthetic capacities and are directly dependent on livingcells to furnish these deficiencies. In other 'words, the very metabolic pathways which are necessary to the life of the plant are also necessary to the life of the parasite. It is apparent, therefore, that any agent that is capable of killing the parasite is potentially capable of killing the plant. In eradicating obligate parasites the parasiticide interferes with a metabolic pathway and/or pathways of the parasite. Some of these pathways the parasite will have in common with the host. In this event the parasiticide must be so specific in its action that it does not interfere with the metabolism of the host to such an extent as to be fatal. Furthermore, since the organism will not grow in artificial media it is necessary to carry out all testing in vivo. Rusts are a diseased condition of plants caused by a class of obligate parasites.

When these facts are considered, it will be apparent that the discovery of the remarkable activity of the compounds of this invention in the control of Wilts and rusts is a most important contribution to the art.

The following experiment is presented to show the unusually high order of activity of the compounds of this invention in the control of rusts. A group of bean plants harboring a very heavy infection of bean rust caused by exposing the plants to the activity of the obligate parasite Uromyces phaseoli (formerly U. appendiculatus) was divided into two smaller groups. One group was treated by spraying with an acetone-water solution containing 80 parts per million of 2-tetradecylamino-4,5,6,7-tetrahydro- 1,3-diazepine hydriodide and a second group was sprayed with an acetone-water solution containing no active agent. This latter group served as a control. It was found that at the end of three days, the disease had almost completely disappeared from those plants sprayed with the active agent of this invention. Similarly, plants sprayed with mixtures containing at little as 80 parts per million of this same active compound were found to be completely free of infection. The control plants completely deteriorated. No injury to the plant was observed during the treatment.

In another experiment, a group of bean plants with a heavy infection of bean mildew caused by Erysiphe polygoni DC was divided into two smaller groups. One group was treated by spraying with an acetone-water solution containing 80 parts per million of Z-decylami-no- 4,5,6,7-tetrahydro-1,3-diazepine 'hydriodide and the second group was sprayed with an acetone-water solution containing no active agent. At the end of three days the results were compared and it was found that, although the mildew had practically disappeared from the treated plants, the infection had increased and multiplied in the controls to the point where they would no longer bear useful produce. The compounds of this invention have an extremely low order of phytotoxicity. This has been established by application of the standard cucumber seed germination test. The germinated cucumber seed is a plant material which is extremely sensitive to inhibitory substances. The tests as carried out use 50 seeds per level of compound. The 50 seeds are mechanically placed in a plastic box containing a non-toxic absorbent paper such as the paper which is commercially available under the name Kem-pack and recommended by the United States Department of Agriculture Seed Laboratory, and 150 ml. of a 5% acetonewater composition containing the compound to be tested is added. After 3 days incubation at 28 C., comparisons are made between the seeds which have been treated with the test composition and seeds which have been identically treated except that the acetone-water solution does not contain any active agent. These latter seeds serve as a control.

When the compounds of this invention were tested according to this procedure, they showed a low order of phytotoxicity. They were tested at concentrations of one, ten and one hundred parts per million. The results of a typical test show from 90 to 94% germination of untreated controls and no decrease in germination by treatment with the compounds under test. No significant decrease was noted in total wet weight. In fiact, with a 2-hexylamino-4,5,6,7-tetrahydro-1,3-diazepine hydriodide there was an actual increase in wet weight at ten and one hundred parts per million.

An anti-pathogenic composition of this invention will contain an efiective amount of the selected amine dispersed in a suitable extending agent.

In this disclosure and in the claims appended thereto the term, dispersed is used in the widest possible sense. It includes particles of molecular size held in true solution in a suitable solvent. It includes particles of colloidal size dispersed in a liquid phase in the form of suspensions or emulsions or in the form of particles which are dispersed in a semi-solid viscous carrier such as petroleum jelly (e.g. sold under the trademark Vaseline) or soap in which case the particles may be actually dissolved in the carrier or held in suspension in the carrier with the aid of suitable emulsifying or wetting agents. The term, dispersing also includes particles which may be mixed with and spread throughout a solid carrier so that the composition is in the form of a powder or dust. Dispersed also includes compositions suitable for use as aerosols such as a solution, suspension or emulsion in a carrier of the Freon type, for example, Freon-l1 '(trichloromonolluoromethane), Freon-12 (dichlorodifluoromethane), Freon-22 (monochlorodifluoromethane), Freon-113 (trichlorotrifluoroethane) or Freon-114 (dichlorotetrafluoroethane).

The term, extending agents as used in this disclosure and in the appended claims includes any and all of the usual economically practical, commercially available extending agents conveniently used in the practice. It includes, therefore, the solvents of a true solution, the liquid phase of suspensions, emulsions or aerosols, the semi-solid carrier of ointments and the solid phase of dust and powders. These agents should, of course, be non-toxic to the host at the levels employed and chemically inert towards the agents of this invention.

It has been found that the active amines and acid addition or quaternary salts of this invention are effective alone or when dispersed in an extending agent at concentrations as low as forty parts per million. This concentration is efliective when the dispersing agent is liquid but it is pre ferred, although not necessary, to use more concentrated mixtures when the dispersing agent is a semi-solid or a solid. This is because liquid dispersions which are, of course, suitable for use as sprays or injectable solutions give more intimate contact of the active material with the host and, therefore, are more effective at lower concentrations.

There are a number of liquid media which can be utilized for the preparation of solutions, suspensions or emulsions containing an active agent of this invention.

'It has been found that high boiling oils of vegetable origin such as castor oil or olive oil are suitable. Low boiling, more volatile solvents such as acetone, cyclohexane, carbon tetrachloride, ethylene dichloride, tetrachloroethane, hydrogenated naphthalenes, solvent naphtha and the like are also useful. Petroleum fractions, particularly kerosene, are especially useful. For certain applications it may be advantageous to resort to mixtures of solvents. If the active agent is to be applied in an aerosol, it is convenient to dissolve it in a suitable solvent and to disperse the resulting solutions in a liquid such as Freon. For such applications it has been found that it is better to employ true solutions of the active agents although it is possible to employ suspensions or emulsions.

The active agents of this invention will often be dispersed either in the form of emulsions or suspensions in an inert carrier such as water with the aid of a capillary active substance. Such capillary substances may be anion-active, cation-active or non-ionizing. There may be mentioned by way of example natural or synthetic soaps, Turkey-red oil, fatty alcohols, sulfonates, esters of fatty acids and the like. Other examples include high gamma 7 molecular weight ammonium compounds as well as con densation products of ethylene and propylene oxide with monohydric and polyhydric alcohols. For use as a powder or dust the compounds can be prepared using any of a number of extending agents either organic or inorganic in nature which are suitable for the manufacture of pulverulent preparations. These include, for example, calcium carbonate, kaolin, bole, kieselguhr, talcum, casein, magnesium carbonate, boric acid and others. Materials of vegetable origin such as powdered cork, powdered wood and powdered walnut shells are also useful. These compositions may be used in the dry form, or by the addition of wetting agents the dried powder can be rendered wettable by water so as to obtain stable aqueous dispersions suitable for use as sprays.

For special purposes it would be advantageous to prepare anti-phytopathogenic compositions in the form of a paste or an ointment by the use of a semi-solid extending agent such as soap or petroleum jelly with or without the aid of solubility promoters and/or dispersing agents.

In all of the forms described above the dispersions may be provided ready for use or they may be provided in a concentrated form suitable for mixing with other extending agents at the time of application.

It is sometimes advantageous to have other active agents, for example, bactericides or insecticides such as pyrethrum, streptomycin, oxytetracycline, D.D.T. (dichlorodiphenyltrichloroethane) malathion or chlordane in the same compositions which contain the active agent or agents of this invention. A composition of this nature has the advantage that two or more active agents can be distributed in one and the same application.

i The amount and concentration of active agent of this invention which will be employed against a particular plant infection will, of course, vary considerably. The type of plant, the type of disease involved, the manner of application, the time of year, weather conditions and state of development of the plant are among the many factors which are to be considered. In general, effective control of various fungal infections is achieved by applying the antiphytopathogenic agent to the habitat of the pathogen or the area to be protected from phytopathogenie attack in concentrations of at least forty parts per million, although higher concentrations even up to eight hundred parts per million can be used.

The agents of this invention are useful in the control of animal pathogens including those which attack humans. It has been found, for example, that the minimuminhibitory concentration of 2-decylaminoimidazolinc hydriodide when tested by the standard agar incorporation technique against the microorganism Blastomyces dermatitidis is only 1 meg/ml. The same result is obtained against this organism with 2-dodecylaminoimidazoline hydriodide.- The minimum inhibitory concentration of Z-tetradecylamino- 1,4,5 ,6-tetrahydropyrimidine against Mycobacterium beralinense is only 3 meg/ml. Similar results are obtained with these and other compounds of this invention when tested against a variety of other pathogens including Micrococccus pyogenes var. aureus and Escherichia coli.

The following examples are given solely for the purpose of illustration and are not to be construed as limita-' tions of this invention, many variations of which are possible without departing from the spirit or scope thereof.

EXAMPLE I 2- tet'radecyla mino-l,4,5,6-tetrahydropyrimidin hydriodide ice cold ether. The mixture was filteredand the desired product dried in vacuo. The procedure of this example was used with appropriate starting materials to prepare the following compounds,

2-hexylamino-l,4,5,6-tetrahydropyrimidine hydriodide 2-octylamino-1,4,5,6-tetrahydropyrimidine hydrochloride 2-decylamino-1,4,5,6-tetrahydropyrimidine hydrofluoride 2 decylamino 1,4,5,6-tetrahydro-S-propylpyrimidine hydrobromide 2-dodecylamino1,4,5,6-tetrahydropyrirnidine hydriodide Z-tetradecylamino-l,4,5,6-tetrahydropyrimidine hydriodide 2 hexadecylamino l,4,5,6-tetrahydropyrimidine hydrochloride v 2 octadecylamino 1,4,5,6 tetrahydropyrimidine hydrobromide I, 2-heptylamino-l,4,5,6-tetrahydropyrimidine hydriodide 2-(2-octenylamino)'-1,4,5,6-tetrahydropyrimidine hydriodide 2-(2,3-dimethyl-decylamino) -1,4,5,6-tetrahydropyrimidine hydrochloride 1 2 octadecylamino 1,4,5 ,6 tetarhydropyrimidine hydrm fluoride 2 tetradecylamino-1,4,5,G-tetrahydro-S-propylpyrimidinc hydrobromide 2- (2-hexenylamino)-1,4,5,6-tetrahydropyrimidine dide I 2-octadecylamino-4,5,6,7-tetrahydro-'1,3-diazepine hydriodide 2-hexylamino-4,5,6,7-tetrahydro-1,3-diazepine hydrochloride 2 nonylamino N-(Z-butenyl)-4,5,6,7-tetrahydro-1,3-diazepine hydrofluoride 2 (2,3-dimethyl-decylamino)-N-ethyl-4,5,6,7-tetrahydro- 1,3-diazepine hydrobromide 2 dodecylamino-5-ethyl-4,5,6,7-tetarahydro-1,3-diazepine hydriodide 2-nonylamino-4,5,6,7-tetrahydro-1,3-diazepine hydriodide 2-occtiylamino-4,5,6,7-tetrahydro-l,3-diazepine hydrochlor1 e 2-hexylarnino-1,3-diazacyclooctene-2 hydrofluoride 2-octadecylamino-l,3-diazacyclooctene-2 hydrobromide I 2 propylamino-N-(3-hexenyl)1,3-diazacyclooctene-2 .hy-I

driodide 2 -dotylamino 4,6-diethyl-1,3-diazacyclooctene-2 hydriohydrio- EXAMPLE II Z-octyl aminoimia'azole hydrobromide A mixture was prepared containing 0.25 mol of 2- aminoimidazole in ml. of ethanol. To this there was added 0.3 mol of octyl bromide in 75 ml. of ethanol. The mixture was allowed to stand at 25 C. for fortyeight hours and the solvent removed in vacuo. The residue was triturated with ice cold hexane and filtered to give the desired compound.

The procedure of this example was used with appropriate starting materials to prepare the following compounds.

EXAMPLE IH 2-teti'adecylamino-1,4,5,6-tetrahydrapyrimidine Z-tetradecylamino-l,4,5,6-tetrahydropyrimidine hydriodide (0.09 mol) was dissolved in 400 ml. of a 1:1 mixture of methanol and water. The solution was poured with stirring into an ice cold solution of 3.65 g. of sodium hydroxide and 2.5 liters of water. The resulting mixture was extracted twice with equal volumes of ether. The ether solution was dried over anhydrous sodium sulfate, filtered and the solvent removed in vacuo to give the desired product.

The acid addition salts prepared in accordance with Examples I and II were all converted to free bases using the foregoing procedure.

EXAMPLE IV Preparation of acid addition salts Each of the free bases prepared in accordance with the preceding example was converted to a variety of acid addition salts using standard procedures for instance, dissolving the free base in ether and forming the acid addition salt by the addition of a water solution containing excess acid. In most instances the acid addition salt precipitated from solution. In a few cases where it did not, it was recovered by evaporating the solvent. Even in those cases where the acid addition salt did precipitate, it was possible to obtain an increased yield by evaporating the solvent. The acid addition salts prepared included nitrates, sulfate, phosphates, acetates, propionates, valerates, benzoates, maleates, sulfonates, gluconates, p-tolue'nesulfonates and butyrates.

EXAMPLE V Preparation of quaternary ammonium halide salts Each of the free bases prepared in accordance with Example II was converted to a methyl, ethyl, propyl or butyl quaternary fluoride, chloride, bromide or iodide by refluxing a methanolic solution containing the free base and a 10% excess of the appropriate alkyl halide. In most instances the quaternary compound precipitated on cooling, but whether it did or did not maximum yields were always obtained by removing the solvent in vacuo.

These compounds were converted to other quaternary alkyl ammonium salts by contacting them in water with a basic anion exchange resin which had been previously treated with aqueous acid. In this manner, a variety of quaternary salts were prepared including the acetate, propionate, valerate, citrate, gluconate, itaconate, maleate, succinate, nitrate, phosphate and sulfate.

EXAMPLE v1 EXAMPLE VII To a mixture containing 25 g. of talcum, 4 g. of sodium dibutyl naphthalene sulfate, 4 g. of casein and 5 g. of sodium carbonate was added suflicient Z-tetradecylamino-l,

4,5,6-tetrahydro 5 propylpyrimidine to provide a mixture containing 200 parts per million of active agent. The mixture was added to an equal quantity of ground calcium carbonate and the whole thoroughly mixed. This powder may be suspended in water immediately before use and gives a fungicidal suspension which is sufliciently stable for use in spraying applications.

EXAMPLE VIII A solution is prepared containing 9 parts per million of 2-propylamino-N-butylimidazole in carbon tetrachloride.

The solution is useful in the treatment of fungal infections by spraying.

EXAMPLE IX A mixture is prepared containing 400 parts per million of 2-undecyl-IO-enylaminoimidazole in a 1:1 mixture of xylene and Turkey-red oil. This solution can be readily emulsified in water and the fungicidal emulsion is suitable as a spray.

EXAMPLE X A solution is prepared containing 800 parts per million of 2-octadecylaminopyrimidine and 5 g. of D.D.T. in g. of kerosene. This solution is useful as a spray in treating fungal infections of plants.

EXAMPLE XI A solution containing 300 parts per million of Z-octadecylamino-4,5,6,7-tetrahydro-1,3-diazepine in 4 g. of acetone and 160 g. of Freon-12 is prepared and used as a fungicidal agent in an aerosol form.

EXAMPLE XII 2 hexylamino 4,5,6,7-tetra.hydro-1,3-diazepine hydrochloride was dispersed with petroleum jelly to give a mix ture which contained 500 parts per million of the active agent. The mixture was found to be effective in treating plants which were infected with late tomato blight.

EXAMPLE XIII EXAMPLE XV Z-dodecylaminb l,4,5,6 tetrahydropyrimidine hydriodicle was dispersed with petroleum jelly to give a mixture which contained 500 parts per million of the active agent.

The mixture was found to be effective in treating plants which were infected with late tomato blight.

EXAMPLE XVI A solution containing 300 parts per million of 2-(2-oc- 'tenylamino)-1,4,5,6 tetrahydropyrimidine hydriod-ide in 4 g. of acetone and 160 g. of Freon-l2 is prepared and used as a fungicidal agent in an aerosol form.

EXAMPLE XVII To a mixture containing g. of pulverized calcium carbonate, 2 g. of olein and one gram slaked lime was added sufiicient Z-decylamino-l,4,5,6-tetrahydro-5-propylpyrimidine hydrobromide to give a mixture containing 100 parts per million of 2 decylaminod,4,5,6-tetrahydro-5- propylpyrimidine hydrobromide and the mixture was ground in a ball mill. The resulting powder is easily scattered, has good adhesive power and is effective against early and late tomato blight.

EXAMPLE XVIII To a mixture containing 25 g. of talcum, 4 g. of sodium dibutyl naphthalene sulfate, 4 g. of casein and 5 g. of sodium carbonate was added suflicient Z-tetradecylamino- 4methylimidazole hydriodide to provide a mixture containing 200 parts per million of active agent. The mixture was added to an equal quantity of ground calcium carbonate and the whole thoroughly mixed. This powder may be suspended in water immediately before use and gives a 1 1 fungicidal suspension which is sufiiciently stable for use in spraying applications.

EXAMPLE XIX A solution is prepared containing 9 parts per million of 2 propylamino N (3-hexenyl)-l,3-diazacyclooctene-2 in carbon tetrachloride. The solution is useful in the treatment of fungal infections by spraying.

EXAMPLE XX A mixture is prepared containing 400 parts per million of 2-(2,3-dimethyldecylarnino)-1,4,5,6-tetra.hydropyrimidine in a 1:1 mixture of xylene and Turkey-red oil. This solution can be readily emulsified in water and the fungicidal emulsion is suitable as a spray.

EXAMPLE XXI A solution is prepared containing 800 parts per million of 2 octadecylamino-1,3-diazacyclooctene-2 and g. of D.D.T. in 90 g. of kerosene. This solution is useful as a spray in treating fungal infections of plants.

EXAMPLE XXII A solution containing 300 parts per million of 2-octylamino-4,5,6,7-tetrahydro1,3-diazepine in 4 g. of acetone and 160 g. of Freon-l2 is prepared and used as a fungicidal agent in an aerosol form.

EXAMPLE XXIII 2-(2-hexenylamino)-l,4,5 ,6 tetrahydropyn'midine hydriodide was dispersed with petroleum jelly to give a mixture'which contained 500 parts per million of the active agent; the mixture was found to be effective in treating plants which were infected with late tomato blight.

EXAMPLE XXIV A solution is prepared containing 800 parts per million of 2-octadecylamino-1,4,5,6-tetrahydropyrimidine and 5 g. of D.D.T. in 90 g. of kerosene. This antifugal solution is useful as a spray.

EXAMPLE XXV A solution containing 300 parts per million of 2-(2,3- dimethyl-decylamino)-N-ethyl-4,5,6,7-tetrahydro 1,3-diazepine hydrobromide in 4 g. of acetone and 160 g. of Freon-l2 is prepared and used as a fungicidal agent in an aerosol form.

EXAMPLE XXVI 2-octylamino-4,6-diethyl-1,3-diazacyclooctene-2 hydriodide was dispersed with petroleum jelly to give a mixture which contained 500 parts per million of the active agent. The mixture was found to be effective in treating plants which were infected with late tomato blight.

EXAMPLE XXVII A solution containing 300 parts per million of 2-nonylamino-N-(Z-bntenyl)-4,5,6,7-tetrahydro-1,3-diazepine hydrofluoride in 4 g. of acetone and 160 g. of Freon-12 is prepared and used as a fungicidal agent in an aerosol form.

EXAMPLE XXVIII Ten liters of distilled water for injection U.S.P., were poured into a twenty liter Pyrex glass bottle. To this water is added suflicient Z-tetradecylamino-l,4,5,6-tetrahydropyrimidine hydriodide to provide a solution containing 350 parts per million of active agent EXAMPLE XXIX A tablet base was prepared by blending the following ingredients in the proportion by weight indicated.

Sucrose, U.S.P. 82.0 Tapioca starch 13.6 Magnesium stearate 4,4

To this blend there is aded a sufiicient amount of 2-dodecylaminoimidazole hydrochloride to provide tablets each containing 400 parts per million of active agent.

EXAMPLE XXX A large number of tomato plants harboring a vigorous late blight was separated into two smaller groups. One group was treated with 2-octylamino-4,5,6,7-tetrahydro- 1,3-diazepine by spraying at a concentration of parts per million. The second group was identically treated with a 5% acetone-water spray containing no active agent. At the end of a five-day period, the treated plants were found to be completely cured. On the other hand, the degree of infection in the control group was rated as severe. The plants had almost completely deteriorated and were no longer capable of producing fruit.

EXAMPLE XXXII A solution containing 300 parts per million of 2-(2- octenylamino)-1,4,5,6-tetrahydropyrimidine tartrate in 4 g. of acetone and g. of Freon-l2 is prepared and used as a fungicidal agent in an aerosol form.

EXAMPLE XXHII 2-dodecylamino 1,4,5,6 tetrahydropyrimidine sulfate was dispersed with petroleum jelly to give a mixture which contained 500 parts per million of the active agent. The mixture was found to be effective in treating plants which were infected with late tomato blight.

EXAMPLE XXXIV A solution containing 300 parts per million of the quarternary butyl bromide salt of 2-octylamino-l,4,5,6- tetrahydropyrimidine in,4 g. of acetone and 160 g. of Freon-12 is prepared and used as a fungicidal agent in an aerosol form.

EXAMPLE XXXV A mixture is prepared containing 400 parts per million of the quaternary ethyl chloride salt of 2-octadecylamino- 4,5,6,7-tetrahydro-1,3-diazepine in a 1:1 mixture of xylene and Turkey-red oil. This solution can be readily emulsified in water and the fungicidal emulsion is suitable as a spray.

EXAMPLE XXXVI A mixture is prepared containing 300 parts per million of 2-dodecy1 amino-l,4,5,6-tetrahydropyrimidine as the quaternary butyl gluconate in kerosene was prepared and successfully utilized in the treatment of fungal infections by spraying.

What is claimed is:

1. An anti-phytopathogenic composition comprising as its essential active ingredient from about 40 parts per million to about 800 parts per million of a compound selected from the group consisting of those having the formula /N R-II\T-C CHX)B and the acid addition salts and quaternary alkyl ammonium salts thereof, said alkyl group containing up to four carbon atoms; wherein R is selected from the group consisting of alkyl and alkenyl groups containing from 1 to 18 carbon atoms; R is selected from the group consisting of hydrogen, alkyl and alkenyl containing from 1 to 6 carbon atoms, the total number of carbon atoms in said R and R groups when R is other than hydrogen being from 7 to 24; X is an integer from 1 to 2; and n is an integer from 2 to 5; the cyclic portion of said compounds forming a conjugated system when X is 1 together with an agriculturally acceptable extending agent.

2. An anti-phytopathogenic composition comprising as its essential active ingredient from about 40 parts per million to about 800 parts per million of a compound selected from the group consisting of those having the formula and the acid addition salts and quaternary alkyl ammoni- 'um salts thereof, said alkyl group containing up to four carbon atoms; wherein R is selected from the group con sisting of alkyl and alkenyl groups containing from 1 to 18 carbon atoms; R is selected from the group consisting of hydrogen, alkyl and alkenyl containing from 1 to 6 carbon atoms, the total number of carbon atoms in said R and R' groups when R is other than hydrogen being from 7 to M; X is an integer from 1 to 2; and n is an integer from 2 to 5; the cyclic portion of said compounds forming a conjugated system when X is 1 together with an agriculturally acceptable solid extending agent.

3. An 'anti-phytopathogenic composition comprising as its essential active ingredient from about 40 parts per 'million to about 800 parts per million of a compound selected from the group consisting of those having the formula and the acid addition salts and quaternary alkyl ammoniurn salts thereof, said alkyl group containing up to four carbon atoms; wherein R is selected from the group consisting of alkyl and alkenyl groups containing from 1 to 18 carbon atoms; R is selected from the group consisting of hydrogen, alkyl and alkenyl containing from 1 to 6 carbon atoms, the total number of carbon atoms in said R and R groups when R is other than hydrogen being from 17 to 24; X is an integer from 1 to 2; and n is an integer from 2 to 5; the cyclic portion of said compounds forming a conjugated system when X is 1 together with an agriculturally acceptable semi-solid extending agent.

4. An anti-phytopathogenic composition comprising as its essential active ingredient from about 40 parts per million to about 800 parts per million of a compound selected from the group consisting of those having the formula and the acid addition salts and quaternary alkyl ammonium halide salts thereof, said alkyl group containing up to 4 carbon atoms; wherein R is selected from the group consisting of alkyl and alkenyl groups containing from 1 to 18 carbon atoms; R is selected from the group consisting of hydrogen, alkyl and alkenyl containing from 1 to 6 carbon atoms, the total number of carbon atoms in said R and R groups when R is other than hydrogen being 7 to 24; X is an integer from 1 to 2; and n is an integer from 2 to 5; the cyclic portion of said compounds forming a conjugated system when X is 1 together with an agriculturally acceptable liquid extending agent.

5. A process of controlling phytopathogenic infection in a host subject to such infection which comprises treating said host with an effective amount of a compound selected from the group consisting of those having the formula and the acid addition salts and quaternary alkyl ammonium halide salts, said alkyl group containing up to four carbon atoms; wherein R is selected from the group consisting of alkyl and alkenyl groups containing from 1 to 18 carbon atoms; R is selected from the group consisting of hydrogen, alkyl and alkenyl containing from 1 to 6 carbon atoms, the total number of carbon atoms in said R and R groups when R is other than hydrogen being from 7 to 24; X is an integer from 1 to 2; and n is an integer from 2 to 5; the cyclic portion of said compounds forming a conjugated system when X is 1.

References Cited in the file of this patent UNITED STATES PATENTS 2,540,170 Law et a1. Feb. 6, 1951 2,738,325 Rydell Mar. 13, 1956 2,802,770 Monroe et a1. Aug. 13, 1957 

1. AN ANTI-PHYTOPATHOGENIC COMPOSITION COMPRISING AS ITS ESSENTIAL ACTIVE INGREDIENT FROM ABOUT 40 PARTS PER MILLION TO ABOUT 800 PARTS PER MILLION OF A COMPOUND SELECTED FROM THE GROUP CONSISTING OF THOSE HAVING THE FORMULA 